Impact of Pyrethroid Plus Piperonyl Butoxide Synergist-Treated Nets on Malaria Incidence 24 Months after a National Distribution Campaign in Rwanda.

Malaria remains a public health priority in Rwanda. The use of insecticide-treated nets (ITNs) is a key malaria prevention tool. However, expanding pyrethroid resistance threatens the gains made in malaria control. In 2018, the Rwandan malaria program strategic approach included the use of newer types of ITNs such as pyrethroid plus piperonyl butoxide (PBO) synergist-treated nets to counter pyrethroid resistance. In February 2020, 5,892,280 ITNs were distributed countrywide; 1,085,517 of these were PBO nets distributed in five districts. This study was a pragmatic observational study that leveraged the 2020 net distribution and routinely collected confirmed malaria cases to determine the impact of PBO nets 1 and 2 years after ITN distribution. No differences were observed in the average net coverage between the PBO and standard net districts. A significant reduction in malaria incidence was reported in both the PBO (P = 0.019) and two control districts that received standard nets (P = 0.008) 1 year after ITN distribution. However, 2 years after, this reduction was sustained only in the PBO (P = 0.013) and not in the standard net districts (P = 0.685). One year after net distribution, all districts had a significant reduction in malaria incidence rate (incidence rate ratio < 1). In the second year, incidence in districts with PBO nets continued to decrease, whereas in districts with standard nets, incidences were similar to predistribution levels. The results indicate that PBO nets are a promising tool to combat pyrethroid resistance in Rwanda, with protective effects of up to 2 years post distribution.

Modeling policy interventions for slowing the spread of artemisinin-resistant pfkelch R561H mutations in Rwanda.

Artemisinin combination therapies (ACTs) are highly effective at treating uncomplicated Plasmodium falciparum malaria, but the emergence of the new pfkelch13 R561H mutation in Rwanda, associated with delayed parasite clearance, suggests that interventions are needed to slow its spread. Using a Rwanda-specific spatial calibration of an individual-based malaria model, we evaluate 26 strategies aimed at minimizing treatment failures and delaying the spread of R561H after 3, 5 and 10 years. Lengthening ACT courses and deploying multiple first-line therapies (MFTs) reduced treatment failures after 5 years when compared to the current approach of a 3-d course of artemether-lumefantrine. The best among these options (an MFT policy) resulted in median treatment failure counts that were 49% lower and a median R561H allele frequency that was 0.15 lower than under baseline. New approaches to resistance management, such as triple ACTs or sequential courses of two different ACTs, were projected to have a larger impact than longer ACT courses or MFT; these were associated with median treatment failure counts in 5 years that were 81-92% lower than the current approach. A policy response to currently circulating artemisinin-resistant genotypes in Africa is urgently needed to prevent a population-wide rise in treatment failures.

Association of Plasmodium falciparum kelch13 R561H genotypes with delayed parasite clearance in Rwanda: an open-label, single-arm, multicentre, therapeutic efficacy study.

BACKGROUND: Partial artemisinin resistance is suspected if delayed parasite clearance (ie, persistence of parasitaemia on day 3 after treatment initiation) is observed. Validated markers of artemisinin partial resistance in southeast Asia, Plasmodium falciparum kelch13 (Pfkelch13) R561H and P574L, have been reported in Rwanda but no association with parasite clearance has been observed. We aimed to establish the efficacy of artemether-lumefantrine and genetic characterisation of Pfkelch13 alleles and their association with treatment outcomes. METHODS: This open-label, single-arm, multicentre, therapeutic efficacy study was done in 2018 in three Rwandan sites: Masaka, Rukara, and Bugarama. Children aged 6-59 months with P falciparum monoinfection and fever were eligible and treated with a 3-day course of artemether-lumefantrine. Treatment response was monitored for 28 days using weekly microscopy screenings of blood samples for P falciparum. Mutations in Pfkelch13 and P falciparum multidrug resistance-1 (Pfmdr1) genes were characterised in parasites collected from enrolled participants. Analysis of flanking microsatellites surrounding Pfkelch13 was done to define the origins of the R561H mutations. The primary endpoint was PCR-corrected parasitological cure on day 28, as per WHO protocol. FINDINGS: 228 participants were enrolled and 224 (98·2%) reached the study endpoint. PCR-corrected efficacies were 97·0% (95% CI 88-100) in Masaka, 93·8% (85-98) in Rukara, and 97·2% (91-100) in Bugarama. Pfkelch13 R561H mutations were present in 28 (13%) of 218 pre-treatment samples and P574L mutations were present in two (1%) pre-treatment samples. 217 (90%) of the 240 Pfmdr1 haplotypes observed in the pretreatment samples, had either the NFD (N86Y, Y184F, D1246Y) or NYD haplotype. Eight (16%) of 51 participants in Masaka and 12 (15%) of 82 participants in Rukara were microscopically positive 3 days after treatment initiation, which was associated with pre-treatment presence of Pfkelch13 R561H in Masaka (p=0·0005). Genetic analysis of Pfkelch13 R561H mutations suggest their common ancestry and local origin in Rwanda. INTERPRETATION: We confirm evidence of emerging artemisinin partial resistance in Rwanda. Although artemether-lumefantrine remains efficacious, vigilance for decreasing efficacy, further characterisation of artemisinin partial resistance, and evaluation of additional antimalarials in Rwanda should be considered. FUNDING: The US President's Malaria Initiative. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Nationwide Remapping of Schistosoma mansoni Infection in Rwanda Using Circulating Cathodic Antigen Rapid Test: Taking Steps toward Elimination.

The field standard for the detection of Schistosoma mansoni infection is Kato-Katz (KK), although it misses many active infections, especially light infections. In 2014, a reassessment of S. mansoni prevalence was conducted in Rwanda using the more sensitive point-of-care circulating cathodic antigen (POC-CCA) rapid assay. A total of 19,371 children from 399 schools were selected for testing for single urine CCA. Of these, 8,697 children from 175 schools were also tested with single stool double-slide KK. Samples from eight of these 175 schools were tested again with CCA and additionally with the highly specific and sensitive up-converting phosphor-lateral flow circulating anodic antigen (UCP-LF CAA) assay. Latent class analysis was applied to all four test results to assess sensitivity and specificity of POC-CCA and estimate the proportion of trace results from Rwanda likely to be true infections. The overall prevalence of S. mansoni infection in Rwanda when CCA trace results were considered negative was 7.4% (school interquartile range [IQR] 0-8%) and 36.1% (school IQR 20-47%) when trace was considered positive. Prevalence by KK was 2.0% with a mean intensity of infection of 1.66 eggs per gram. The proportion of active infections among children diagnosed with CCA trace was estimated by statistical analysis at 61% (Bayesian credibility interval: 50-72%). These results indicate that S. mansoni infection is still widespread in Rwanda and prevalence is much underestimated by KK testing. Circulating cathodic antigen is an affordable alternative to KK and more suitable for measuring S. mansoni prevalence in low-intensity regions.

Efficacy of artemether-lumefantrine versus dihydroartemisinin-piperaquine for the treatment of uncomplicated malaria among children in Rwanda: an open-label, randomized controlled trial.

BACKGROUND: Artemisinin-based combination therapies (ACTs) have proven highly effective in reducing malaria morbidity in sub-Saharan Africa. Artemether-lumefantrine (AL) was introduced in 2005 as a first-line ACT for the treatment of uncomplicated malaria in Rwanda. Monitoring the therapeutic efficacy of ACTs is necessary to ensure effective malaria case management. METHODS: A comparative study on the efficacy of AL and dihydroartemisinin-piperaquine (DHP) was conducted in two sites, Masaka and Ruhuha, between September 2013 and December 2015. Clinical and parasitological responses were assessed at days 28 and 42. RESULTS: A total of 534 children were treated with AL (n=267) or DHP (n=267). After polymerase chain reaction (PCR) adjustment, 98.3% and 98.9% of children in the AL and DHP arms, respectively, achieved an adequate clinical and parasitological response (ACPR) at day 28. At day 42, PCR-adjusted ACPR proportions were 97.3% and 98.4% for AL and DHP, respectively. PCR-adjusted ACPR was 99% for both drugs at days 28 and 42 in Ruhuha. The PCR-adjusted ACPR proportions in Masaka were 97.3% for AL and 98.5% for DHP at day 28 and 95.2% for AL and 97.5% for DHP at day 42. CONCLUSIONS: AL remains efficacious in Rwanda 10 y after its adoption. The probability of new infections occurring among patients in the DHP arm was significantly lower than those in the AL arm. DHP also demonstrated a greater post-treatment prophylactic effect against new infections compared with AL.

Polyparasite helminth infections and their association to anaemia and undernutrition in Northern Rwanda.

BACKGROUND: Intestinal schistosomiasis and soil-transmitted helminth (STH) infections constitute major public health problems in many parts of sub-Saharan Africa. In this study we examined the functional significance of such polyparasite infections in anemia and undernutrition in Rwandan individuals. METHODS: Three polyparasite infection profiles were defined, in addition to a reference profile that consisted of either no infections or low-intensity infection with only one of the focal parasite species. Logistic regression models were applied to data of 1,605 individuals from 6 schools in 2 districts of the Northern Province before chemotherapeutic treatment in order to correctly identify individuals who were at higher odds of being anaemic and/or undernourished. FINDINGS: Stunted relative to nonstunted, and males compared to females, were found to be at higher odds of being anaemic independently of polyparasite infection profile. The odds of being wasted were 2-fold greater for children with concurrent infection of at least 2 parasites at M+ intensity compared to those children with the reference profile. Males compared to females and anaemic compared to nonanaemic children were significantly more likely to be stunted. None of the three polyparasite infection profiles were found to have significant effects on stunting. CONCLUSION: The present data suggest that the levels of polyparasitism, and infection intensities in the Rwandan individuals examined here may be lower as compared to other recent similar epidemiological studies in different regions across sub-Saharan Africa. Neither the odds of anaemia nor the odds of stunting were found to be significantly different in the three-polyparasite infection profiles. However, the odds of wasting were higher in those children with at least two parasites at M+ intensity compared to those children with the reference profile. Nevertheless, despite the low morbidity levels indicated in the population under study here, we recommend sustainable efforts for the deworming of affected populations to be continued in order to support the economic development of the country.